Throughout this application, various publications are referred to by superscript Arabic numerals. Full bibliographic citations for these publications are set forth at the end of the application, immediately preceding the claims. The disclosures of these publications are hereby incorporated by reference.
Cholestatic liver diseases, or cholestasis, are a group of disorders of varying causes that result when bile flow is impaired. Cholestasis can cause progressive liver damage and eventually lead to end-stage liver disease. The mechanisms by which the liver is injured and fibrosis is stimulated in cholestatic liver disease are unclear.
Bile flow through the liver may be impaired at any point from the liver cell (hepatocyte) to the ampulla of Vater. For clinical purposes a distinction between intra and extrahepatic causes of cholestasis is helpful.
The most common intrahepatic causes of cholestasis in adults are viral or other hepatitis, drugs and alcoholic liver disease. Less common etiologies include primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis of pregnancy, metastatic carcinoma, and numerous uncommon disorders. In addition, neonatal hepatitis, Alagille Syndrome, Byler's disease, Cystic Fibrosis and other familial cholestatic disorders are the most common intrahepatic forms in children.
Extrahepatic cholestasis is most often caused by a common bile duct stone or pancreatic carcinoma in adults. Less often, benign stricture of the common duct (usually related to prior surgery), ductal carcinoma, pancreatitis or pancreatic pseudocyst, and sclerosing cholangitis are causes. In children, extrahepatic biliary atresia, choledochal cyst, common bile duct stones or strictures and primary sclerosing cholangitis are the most common causes of extrahepatic cholestasis.
Cholestasis results from bile secretory failure; the mechanisms are complex, even in mechanical obstruction. Contributing factors include interference with microsomal hydroxylating enzymes with the attendant formation of poorly soluble bile acids; impaired activity of Na.sup.+, K.sup.+ -ATPase, which is necessary for canalicular bile flow, altered membrane lipid composition and fluidity; interference with the function of microfilaments (thought to be important for canalicular function); and enhanced ductular reabsorption of bile constituents.
The pathophysiologic effects of cholestasis result from backup of bile constituents into the liver and the systemic circulation and their failure to enter the gut for excretion. Bilirubin, bile salts, and lipids are the most important constituents affected. Bilirubin retention produces mixed hyperbilirubinemia with spillover of conjugated pigment into the urine; stools are often pale because less bilirubin reaches the gut. Since bile salts are needed for absorption of fat and Vitamin K, impairment of biliary excretion of bile salts can produce steatorrhea and hypoprothrombinemia. If cholestasis is long-standing, concomitant calcium and Vitamin D malabsorption may eventually result in osteoporosis or osteomalacia. Vitamin A and Vitamin E malabsorption also occur in cholestasis, leading to clinical deficiency states for these vitamins. Cholesterol and phospholipid retention produce hyperlipidemia, though increased hepatic synthesis and decreased plasma esterification of cholesterol also contribute; triglyceride levels are largely unaffected. The lipids circulate as a unique, abnormal low-density lipoprotein called lipoprotein-X.
Jaundice, dark urine, pale stools, and generalized pruritus are the clinical hallmarks of cholestasis. Chronic cholestasis may produce muddy skin pigmentation, excoriations from pruritus, a bleeding diathesis, bone pain, and cutaneous lipid deposits (xanthelasma or xanthomas). These features are independent of the etiology. Any abdominal pain, systemic symptoms (e.g., anorexia, vomiting, fever), or additional physical signs reflect the underlying cause rather than cholestasis itself and therefore provide valuable etiologic clues.
Extrahepatic biliary obstruction usually requires intervention: surgery, endoscopic extraction of ductal stones, or insertion of stents and drainage catheters for strictures (often malignant) or partially obstructed areas. For nonoperable malignant obstruction, palliative biliary drainage can usually be attained via transhepatically or endoscopically placed stents. Endoscopic papillotomy with stone extraction has now largely replaced laparotomy in patients with retained common duct stones. For selected large ductal stones, biliary lithotripsy may be necessary to assist extraction of the fragments; sometimes they pass spontaneously.
Laparotomy is contraindicated in intrahepatic cholestasis; treating the underlying cause may suffice. Pruritus in irreversible disorders (e.g., primary biliary cirrhosis) usually responds to cholestyramine, which binds bile salts in the intestine. Unless severe hepatocellular damage is present, hypoprothrombinemia usually improves after phytonadione (Vitamin K1) therapy. Supplements of calcium and Vitamin D are often given in cases of long-standing irreversible cholestasis, but their impact on retarding metabolic bone disease is negligible. Vitamin A and water-soluble Vitamin E supplements will prevent deficiency of these fat-soluble vitamins, and severe steatorrhea can be minimized by partial replacement of dietary fat with medium-chain triglycerides.
However, chronic cholestatic liver diseases (including primary biliary cirrhosis, primary sclerosing cholangitis, extrahepatic biliary atresia, idiopathic neonatal hepatitis, Byler's disease, and arteriohepatic dysplasia) are a common cause of morbidity (and previously of mortality) and a leading indication for liver transplantation in children and adults..sup.1,2 Current treatment for cholestatic disorders centers on increasing bile flow (1) to reduce pruritus and hypercholesterolemia, (2) to improve intestinal absorption of dietary lipid and fat-soluble vitamins, and (3) theoretically, to reduce the accumulation of hepatotoxic substances (e.g., bile acids) and retard progression to portal fibrosis, cirrhosis, and end-stage liver disease..sup.3,4 The most promising therapy in this regard is the use of ursodeoxycholic acid,.sup.3-6 a hydrophilic bile acid that has hepatoprotective as well as choleretic effects..sup.7,8 However, it is unclear whether current therapies are effective in significantly altering the overall progressive course of cholestatic disorders and resulting liver injury and the need for liver transplantation.
Development of new therapies for chronic cholestasis must be based on the underlying cellular and molecular events by which cholestasis causes liver damage.
Although many pathological processes may result in cholestasis as discussed above (e.g., structural, immunologic, genetic, and inflammatory), one of the postulated final common pathways leading to cholestatic liver injury is the intracellular accumulation of hydrophobic (toxic) bile acids..sup.9-12 The present inventor has previously suggested that oxidant stress may play a role in cholestatic hepatic injury.sup.13 and that hydrophobic bile acids may be capable of initiating the generation of free radicals in the hepatocyte..sup.14 Support for this hypothesis was obtained in a bile duct-ligated rat model of cholestasis in which increased lipid peroxidation (oxidant damage) of hepatic mitochondria was correlated with the severity of cholestatic liver injury,.sup.13 and in isolated rat hepatocytes exposed to bile acids..sup.14
In summary, cholestatic liver disorders are a significant clinical problem in infants, children and adults.sup.1,2,3. Current medical therapies for cholestasis frequently fail to prevent the progression to cirrhosis and the other complications that occur in most patients. In 1993, approximately 270 adults and children underwent liver transplantation because of the complications of cholestatic disorders, at an estimated cost of over $40,000,000.sup.23. Thus, there is a considerable need for the development of new approaches to medical treatment of chronic cholestasis.
The present invention uses nutritional antioxidants to reduce free radical damage to the liver in clinical cholestasis, including alcoholic liver disease. Because low plasma levels of the three proposed antioxidants likely exist in persons with cholestasis, the invention provides moderately high doses of the antioxidants to correct any deficiencies and achieve above-normal blood levels of Vitamin E and beta carotene and higher than normal selenium levels. In a further aspect of the invention, antioxidant compositions are provided that can potentially aid recovery of injured hepatocytes so that these cells can generate endogenous antioxidants, particularly alpha-tocopherol. The solutions of the invention will be used to prevent and treat damage from cholestatic liver diseases of adults and children. The antioxidant compositions can reduce liver injury and thus slow down or prevent the progressive nature of cholestasis.